Mitochondrial dysfunction is an early pathological event in the Alzheimer’s disease (AD) brain. Defects in brain energy metabolism and key respiratory enzyme activity, increased mitochondrial oxidative stress, and alterations in mitochondrial structure, including in the mitochondrial permeability transition pore, occur in the AD-affected regions. However, the mechanisms underlying mitochondrial damage and its association with AD pathology are poorly understood. The questions of whether and how targeting mitochondria serve as a therapeutic strategy for AD are worth addressing.

This recent study led by Hemachandra Reddy at Oregon Health and Science University supports the concept that mitochondrial oxidative stress plays a primary role in amyloid pathology and cognitive decline in AD. The researchers have extensively analyzed the protective effects of the mitochondria-targeted antioxidant catalase (MCAT) and lifespan extension in mice expressing Aβ (Tg2576 mice) from birth to death. They provide substantial evidence that increased MCAT blunts not only oxidative stress and oxidative DNA damage, but also brain Aβ accumulation. Interestingly, MCAT also interferes with APP processing and Aβ production/accumulation by a reduction in the levels of full-length APP, CTF99, BACE1, and Aβ levels, and increased levels of soluble APPα, CTF83, and the Aβ-degrading enzymes neprilysin and insulin-degrading enzyme. Consistent with published studies (Schriner et al., 2005), lifespan extends four to five months in MCAT mice and double MCAT/APP mice compared to the non-Tg and single APP mice, respectively.

These data significantly enhance our understanding of the contribution of mitochondrial reactive oxygen species to aging and AD-etiopathology. Mitochondrial oxidative stress could be an upstream modulator of amyloid pathology and APP processing, leading to impaired learning and memory in AD sufferers. Thus, mitochondria-targeted molecules, such as oxidative stressors or antioxidants, may be effective approaches for halting and preventing AD progression. Increasing antioxidants, such as catalase, at the early stage of AD might be one of the therapeutic approaches for prevention and treatment of the disease.